Skin ulcers are a significant clinical problem and can cause even more serious complications such as, for example, gangrene, systemic inflammatory syndrome, and sepsis. When these complications occur in skin ulcers on the extremities current treatment regimens may require amputations including above-the-knee leg amputation (AKA), below-the-knee leg amputations (BKA), and digital amputations with their obvious implications for the patient.
Skin ulcers have many causes, including venous insufficiency, arterial insufficiency, ischemic pressure, and neuropathies. Venous skin ulcers are the most common type of leg skin ulcers with women affected more than men. Venous skin ulcers are associated with venous hypertension and varicosities. Typically, venous skin ulcers are shallow and painful. Arterial skin ulcers are typically found in elderly patients with history of cardiac or cerebrovascular disease, leg claudication, impotence, and pain in distal foot. Concomitant venous disease is present in up to 25% of cases with an arterial ulcer. Pressure skin ulcers result from tissue ischemia. Pressure skin ulcers are commonly deep and often located over bony prominences. Neuropathic skin uclers are associated with trauma, prolonged pressure, usually plantar aspect of feet in patients with, for example, diabetes, neurologic disorders or Leprosy.
Venous insufficiency is a common cause of lower extremity skin ulcers, accounting for up to 80% of all cases. Of the approximately 7 million people in the United States with venous insufficiency, approximately 1 million develop venous leg ulcers. The cost of venous leg ulcers is estimated to be $1 billion per year in the United States and the average cost per patient exceeds $40,000. Venous skin ulcers are more common with increasing age, with peak prevalence between 60 and 80 years of age. However, younger patients also develop venous skin ulcers resulting in significant morbidity and time away from work. de Araujo et al., Ann. Intern. Med. 2003 138(4):326-34.
Pressure skin ulcers are another major cause of morbidity in older people and the most important care problem in nursing home residents dramatically increasing the cost of medical and nursing care. In particular, pressure skin ulcers of the foot are very common and are difficult to heal among elderly immobilized patients. Pressure skin ulcers at the malleolus, heel, or both develop as a result of pressure, shear, or friction concentrated on a small area over a bone prominence that lacks subcutaneous tissue. An untreated pressure skin ulcer may worsen and lead to cellulitis, chronic infection, or osteomyelitis. Landi et al., Ann. Intern. Med. 2003 139(8):635-41.
Diabetes is also a frequent cause of foot skin ulcers. The prevalence of diabetes in the U.S. is currently about 6%, or over 18 million people, including about 5 million undiagnosed people. In addition, type-2 diabetes appears to be increasing in the U.S. Diabetes is the leading nontraumatic cause of amputation in the U.S. The total number of lower-extremity amputations (LEAs) in diabetic patients in the U.S. is over 80,000 annually. The 3-year mortality rate after a diabetic LEA is between 35 and 50%. Direct costs for diabetic LEAs in the U.S. range from $22,700 for a toe amputation, to $51,300 for an above-the-knee amputation in 2001 dollars. Foot skin ulcers precede about 85% of LEAs in patients with diabetes. The 1-year incidence of new foot skin ulcers in patients with diabetes in the U.S. ranges from 1.0 to 2.6%. V. R. Driver et al., Diabetes Care 2005 28:248-253.
The conventional treatment of diabetic foot ulcers includes debridement, revascularization, dressings, and the treatment of any infections present. Debridement should remove all debris and necrotic material to render infection less likely. The common recommendation is that nonadherent dressings should cover diabetic foot ulcers at all times and occlusive dressings may lower the risk of infection.
Both wet and dry gangrene can occur in the diabetic foot. Wet gangrene is caused by a septic arteritis, secondary to soft-tissue infection or ulceration. Dry gangrene is secondary to a severe reduction in arterial perfusion and occurs in chronic critical ischemia. Revascularization followed by surgical debridement is recommended for the treatment of foot ulcers in diabetics. Although antibiotics are a critical component of the therapy, treatment of infection with antibiotics alone is usually insufficient to resolve the majority of diabetic foot infections. American Diabetes Association Consensus Statement, Diabetes Care 2003 26:3333-3341. Accordingly, there is particularly a need for additional methods of treatment of foot skin ulcers in diabetics.
The spectrum of chronic skin ulcers in which infection plays a clinical role includes critical limb ischemia (CLI), diabetic foot ulcers, below-knee amputations (BKA), methicillin-resistant Staphylococcus aureus (MRSA), and chronic venous insufficiency (CVI). The role of infection in these conditions may range from minor to severe, but it likely plays a significant role in most cases. Infected skin ulcers often require systemic antibiotics and, when present in the extremities, may require amputations.
There is a need to develop treatments of skin ulcers that reduce the need for amputation. In patients over 85 years of age, primary amputation (PA) still carries an excessively high mortality rate of 13-17%. In the highest risk patients, 30-day periprocedural mortality after amputation can range from 430% and morbidity from 20-37%, because many endstage. CLI patients will suffer from infection, sepsis, and progressive renal insufficiency. Successful rehabilitation after BKA is achieved in less than two-thirds of patients; after above-the-knee amputations, that fraction is less than one-half of patients. Overall, less than 50% of all patients requiring amputation ever achieve full mobility. There is a poor overall prognosis for the CLI patient with mortality rates greater than 50% after 3 years and twice the mortality rate after BKA versus limb salvage. In addition, the total cost of treating CLI in the United States is estimated at $10-20 billion per year. Similarly, the annual cost of follow-up or long-term care and treatment for an amputee is significantly greater than if the limb is salvaged.
Depending on the type and severity of the ulcer, the clinical picture could progress to an acute systemic inflammatory response syndrome (SIRS), sepsis or septic shock. The systemic inflammatory response syndrome (SIRS), a syndrome that encompasses the features of systemic inflammation without end-organ damage or identifiable bacteremia. SIRS is separate and distinct from sepsis, severe sepsis or septic shock. The key transition from SIRS to sepsis is the presence of an identified pathogen in the blood. The pathophysiology of SIRS includes, but is not limited to, complement activation, cytokine and arachidonic acid metabolites secretion, stimulated cell-mediated immunity, activation of the clotting cascades, and humoral immune mechanisms. Clinically SIRS is characterized by tachycardia, tachypnea, hypotension, hypoperfusion, oliguria, leukocytosis or leukopenia, pyrexia or hypothermia, metabolic acidosis, and the need for volume support. SIRS may affect all organ systems and may lead to multiple organ dysfunction syndrome (MODS). Thus, even in early stages (i.e. SIRS), there is accumulation of pro-inflammatory cytokines at the site of the ulcer and in the blood that contribute to the establishment of multi-organ failure and death.
Accordingly, there remains a need for new methods of treating skin ulcers. The invention provides such methods. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.